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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emanating human infectious coronavirus that causes COVID-19 disease. On 11th March 2020, it has been announced as a pandemic by the World Health Organization (WHO). Recently, several repositioned drugs have been subjected to clinical investigations as anti-COVID-19 drugs. Here, in silico drug discovery tools were utilized to evaluate the binding affinities and features of eighteen anti-COVID-19 drug candidates against SARS-CoV-2 main protease (Mpro). Molecular docking calculations using Autodock Vina showed considerable binding affinities of the investigated drugs with docking scores ranging from − 5.3 to − 8.3 kcal/mol, with higher binding affinities for HIV drugs compared to the other antiviral drugs. Molecular dynamics (MD) simulations were performed for the predicted drug-Mpro complexes for 50 ns, followed by binding energy calculations utilizing molecular mechanics-generalized Born surface area (MM-GBSA) approach. MM-GBSA calculations demonstrated promising binding affinities of TMC-310911 and ritonavir towards SARS-CoV-2 Mpro, with binding energy values of − 52.8 and − 49.4 kcal/mol, respectively. Surpass potentialities of TMC-310911 and ritonavir are returned to their capabilities of forming multiple hydrogen bonds with the proximal amino acids inside Mpro's binding site. Structural and energetic analyses involving root-mean-square deviation, binding energy per-frame, center-of-mass distance, and hydrogen bond length demonstrated the stability of TMC-310911 and ritonavir inside the Mpro's active site over the 50 ns MD simulation. This study sheds light on HIV protease drugs as prospective SARS-CoV-2 Mpro inhibitors. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (Mpro) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 Mpro using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards Mpro with docking scores less than −9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with Mpro. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 Mpro over 150 ns MD course with Δ G binding values of −69.0 and −68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 Mpro active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 Mpro inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations. [Display omitted] • A database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 Mpro using in silico techniques. • PubChem-129-716-607 and PubChem-885-071-27 demonstrated higher binding affinities against Mpro than rutin and baicalein. • PubChem-129-716-607 and PubChem-885-071-27 exhibited high stability inside the Mpro active site over 150 ns MD simulations. • PubChem-129-716-607 and PubChem-885-071-27 manifested promising drug-likeness properties. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ −40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of −51.9 vs. −33.6 kcal/mol, respectively. Protein–protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target–function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing. [ABSTRACT FROM AUTHOR]